The relationship between C‐reactive protein and levels of various cytokines in patients with COVID‐19: A systematic review and correlation analysis

C‐reactive protein (CRP) and cytokines levels could alter in patients with coronavirus disease (COVID‐19) due to the inflammatory response caused by the virus. This analysis aimed to assess the relationship between the CRP levels and the levels of various cytokines in COVID‐19 patients.


| INTRODUCTION
The coronavirus disease , caused by acute respiratory dysfunction coronavirus 2 (SARS-CoV-2), has been pandemic across the countries. 1 It is still pandemic around the world. Many people experience mild to moderate symptoms, but some also suffer from severe symptoms and even death.
Common symptoms of COVID-19 include fever, cough, myalgia, fatigue, or respiratory distress. In severe cases of the disease, dyspnea and respiratory problems occur and cause acute respiratory distress syndrome (ARDS) or multiple organs. 1 Following the proliferation of the virus, the host's immune system is also activated to fight the virus and cure the patient, however some patients develop severe and disease such as MODS, The cause is still unknown. 2,3 Recent studies have showed that, in addition to common symptoms, untreated inflammation contributes to disease severity in  For those infected by SARS-CoV-2, some of the patients did not show dispnea or respiratory distress during the COVID-19, indicating a multifaceted disease of COVID-19 infection. The prognosis for patients is not fully understood, and the type and severity of the consequences of COVID-19 may depend, inter alia, on the severity of the course of the infection, age, and comorbidities. 2 Extreme COVID-19 is characterized by interleukin waves, organ dysfunction disease, and destruction of many metabolic processes, including coagulation factors and blood clotting. 3 Therefore, a reliable and appropriate test is needed to predict the severity of COVID-19 disease. 2 Recently, several studies have reported that C-reactive protein (CRP) is directly associated with the severity of infection, and patients with higher CRP in the early stages of the disease are at greater risk for severe disease. 5 CRP, first described by Tillet and Francis, is released from the liver in response to interleukin-6 (IL-6) and it is an inflammatory test that is available everywhere. Many studies have also shown that the level of this biomarker is associated with the severity of influenza, and recently some studies have reported an association between CRP levels with the severity of COVID-19 disease. 6

| MATERIALS AND METHODS
This analysis orchestrated to reflect on the potential correlations between CRP and various cytokines levels in patients with COVID-19 based on current evidence. To ensure the validity and authenticity of this report, we adhered to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) checklist as illustrated in Figure 1. To refrain the included studies from bias risk we utilized the Newcastle-Ottawa Scale (NOS) with three categories (maximum scoring for each category in the following parentheses) of selection, 3 comparability, 4 and exposure/outcome 2 and total scoring of 9 (see Table 1). "COVID-19" OR "SARS-CoV-2" OR "SARS-CoV2" OR "2019-nCoV" OR "Novel Coronavirus" [title/abstract] "CRP" OR "CRP" OR "Cytokine" OR "Interleukin" OR "Chemokine" OR "Lymphokine" OR "Interferon" OR "IFN" OR "Tumor necrosis factor" OR "TNF" OR "Monokine" [title/abstract]

| Sample and data
We conducted a two-phase screening process. First, the title and abstract of the studies were evaluated according to the inclusion criteria. Then, the full-text of the studies was carefully investigated and the eligible studies were included for the qualitative synthesis.
Original studies that assessed CRP and the level of at least one cytokine in patients with COVID-19 were included in this analysis.
The exclusion criteria were as follows: (1) Nonoriginal articles; for example, reviews, systematic reviews, or meta-analyses

| Measures and variabales
Following summarizing the included papers, cumulative distribution of participants' characteristics including gender, mean age, severity of symptoms, advanced procedures applications, patient outcome, administered medications, comorbidities, various laboratory values, CRP level, and all the reported cytokines were collected and organized in a specifically designed sheet (Table 2). Four investigators independently prepared and cross-checked this information. Other researchers went through the selected studies and accumulated data to avoid any probable duplications and crossovers.

| Data analysis procedure
This study examined the correlation between CRP and levels of various cytokines in patients with COVID-19. First, we determined the aggregate mean and standard deviation (SD) of all the variables for which data were sought. The correlation between different Interleukins and CRP levels was measured using the correlationcoefficient (r) and p-value. A significant relationship was defined as: All the statistical analyses were conducted using SPSS software version 26.

| RESULTS
Our initial search yielded 1307 records, of which 506 were duplicates and 801 records entered the title and abstract screening. Screening the title/abstract; 615 records were removed and 186 were eligible for full-text screening. Finally, we found 103 eligible studies accounting for 101,309 total participants in the analysis (Figure 1).
F I G U R E 1 Preferred reporting items for systematic reviews and meta-analyses 2020, flow diagram for systematic literature review The patients were mostly males older than 50 years suffering  Table 2.
In Table 3, distribution of some variables based on median and interquartile range has also been reported.  preventing disease deterioration. 22,23,26 As such, there is a link discovered between IL-6 levels and lymphocyte count, LDH, CRP, and procalcitonin. With high sensitivity and specificity, the optimal IL-6 cutoff value has been suggested to be 30.95 pg/ml. 24,[27][28][29][30][31][32][33][34][35][36][37] Interestingly, elevated serum levels of CRP and lactate dehydrogenase (LDH) seem to exhibit a significant reduction after antiviral therapy but serum levels of proinflammatory markers like IL-6, IL-8, and IFNγ remain elevated at baseline in COVID-19 patients. 15 Furthermore, dynamic cytokine storms as well as high serum IL-6 and TNF-serum levels, were found to be independent and significant predictors of disease severity and death. 4